Abstract: Chemical Biology Facility (ChBF) The Chemical Biology Facility (ChBF) is a major, cancer-focused component of the University of Pittsburgh Drug Discovery Institute (UPDDI) with the following Specific Aims: 1) provide assistance to designing, developing, and implementing cost effective screening assays as well as access to large compound libraries for probe and lead identification. This includes assisting with early toxicity assays for profiling compounds; 2) guide collaborators in designing effective drug discovery projects/programs for the discovery of novel cancer therapeutics; and 3) provide access to the state-of-the-art use of QSP in implementing novel drug discovery campaigns. The ChBF provides guidance on designing and executing drug discovery and development projects from target and lead discovery through preclinical development. The ChBF provides support services to UPCI researchers for: 1) high throughput screening and high content screening assay design, development, validation, and implementation; 2) lead characterization and optimization including early safety assessment; 3) data analysis; 4) accessing companion diagonstic opportunities; 5) assisting investigators in establishing connections with pharmaceutical companies; and 6) designing comprehensive drug discovery/development programs. The ChBF has added several early safety assessment assays to its armamentarium to aid researchers in the early triage of compounds during drug development including a zebrafish cardiotox assay, liver toxicity assay, and a microsomal stability assay. We have also implemented zebrafish imaging assays to enable higher throughput vertebrate models for drug discovery and development, as well as tissue engineered, human 3-D, biomimetic models (e.g. liver). A key addition made to the ChBF services is the implmentation of Quantitative Systems Pharmacology (QSP) as a new approach to drug discovery. QSP is an approach to drug analysis and development that combines computational and experimental methods to elucidate, validate, and apply new pharmacological concepts to the development and use of therapeutics. Additionally, the ChBF has developed and implemented methods to assess heterogeneity in biological systems to help researchers better understand the activity of compounds in their models. During the current project period investigators in 8 of the UPCI Research Programs used the ChBF.